6-8026378-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201280.3(BLOC1S5):c.373G>C(p.Glu125Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000484 in 1,610,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: BLOC1S5 NM_201280.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

Genes affected

BLOC1S5 (HGNC:18561): (biogenesis of lysosomal organelles complex 1 subunit 5) This gene encodes a component of BLOC-1 (biogenesis of lysosome-related organelles complex 1). Components of this complex are involved in the biogenesis of organelles such as melanosomes and platelet-dense granules. A mouse model for Hermansky-Pudlak Syndrome is mutated in the murine version of this gene. Alternative splicing results in multiple transcript variants. Read-through transcription exists between this gene and the upstream EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) gene, as well as with the downstream TXNDC5 (thioredoxin domain containing 5) gene. [provided by RefSeq, Dec 2010]

BLOC1S5-TXNDC5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16555253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S5	NM_201280.3	c.373G>C	p.Glu125Gln	missense_variant	4/5	ENST00000397457.7
BLOC1S5-TXNDC5	NR_037616.1	n.411G>C		non_coding_transcript_exon_variant	4/13
EEF1E1-BLOC1S5	NR_037618.1	n.719G>C		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S5	ENST00000397457.7	c.373G>C	p.Glu125Gln	missense_variant	4/5	1	NM_201280.3	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000679 AC: 17 AN: 250276 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135308

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1458650 Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25 AN XY: 725792

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000991

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74342

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000614 Hom.: 0

Bravo AF: 0.000574

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2021

The c.373G>C (p.E125Q) alteration is located in exon 4 (coding exon 4) of the BLOC1S5 gene. This alteration results from a G to C substitution at nucleotide position 373, causing the glutamic acid (E) at amino acid position 125 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.085	T
Sift4G	Benign	0.096	T
Polyphen		1.0	D
Vest4		0.49
MVP		0.43
MPC		0.29
ClinPred		0.20	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs369022314; hg19: chr6-8026611;